21-phosphate esters of 17{60 -acyloxy-21 hydroxy steroids of the pregnane series

ABSTRACT

This invention is concerned with novel 21-phosphate esters of 17 Alpha -acyloxy-21-hydroxy steroids of the pregane series and with methods of preparing such compounds. The compounds are useful as topical anti-inflamatory agents.

United States Patent [191 Elks et al.

[ Oct. 9, 1973 ZI-PHOSPHATE ESTERS OF l7a-ACYLOXY-2l HYDROXY STEROIDS OFTHE PREGNANE SERIES [75] Inventors: Joseph Elks, London; Peter John May,Harrow; Gordon Hanley Phillipps, Greenford, all of England [73]Assignee: Glaxo Laboratories Limited,

Greenford, Middlesex, England 221 Filed: on. 14,1969

[21] Appl. No.: 866,385

[30] Foreign Application Priority Data 3,053,834 9/1962 Fried 260/239.552,789,117 4/1957 Sarett 260/397 .45 3,073,816 1/1963 lrmscher 260/239.53,064,016 11/1962 Vermehren et al 260/397.45

FOREIGN PATENTS OR APPLICATIONS 280,179 1/1965 Australia 260/397.45

2,022,695 11/1970 Germany 260/397.45 792,233 8/1968 Canada 260/397.451,365,253 5/1964 France 260/397.45

OTHER PUBLICATIONS Fried et al., Journ. Amer. Chem. Soc., Vol. 77, 8/55,pp. 4181-4182.

Primary Examiner-Lewis Gotts Assistant ExaminerEthel G. LoveAttorney-Bacon and Thomas [5 7] ABSTRACT This invention is concernedwith novel 21-phosphate esters of l7a-acy1oxy-2l-hydroxy steroids of thepregane series and with methods of preparing such compounds. Thecompounds are useful as topical antiqflam torxs ms-w 6 Claims, NoDrawings ZhPHQSPHALE E TE SQE 7.!-A.QYLQXX 1 .1

HYDROXY STEROIDS OF THE PREGNANE SERIES In British Patent SpecificationNo.l,047,5 l 8 we have described and claimed certain l7a-monoesters 'ofbetamethasone and its 9a-chloro analogue, which compounds haveconsiderably enhanced anti-inflammatory action following topicalapplication as compared with other closely analogous compounds and/orthe corresponding l7a,2l-dihydroxy parent steroids. One such compound,namely betamethasone l7'a-valerate has now been widely used in thetopical treatment of inflammations.

The compounds described in our said specification are substantiallyinsoluble in water and therefore their formulation into preparationssuitable for otic and ophthalmic use presents problems. Sinceantiinflammatory steroids are useful for local application for otic andophthalmic purposes, water-soluble compounds having a high topicalanti-inflammatory action are highly desirable.

We have now found that certain Zl-phosphate esters related to thecompounds described in our said specification form readily water-solublesalts, while at the same time exhibit high topical anti-inflammatoryaction. This combination of properties could not be predicted, sincehigh topical anti-inflammatory action of Where the group R in formula Iis an alkanoyl group, such group preferably contains in general at leastthree carbon atoms.

The group R may be a straight or branched chained alkanoyl group, in thelatter case the isocompounds being preferred. Representative groups forR thus include theacetyl, propionyl, butyryl, isobutyryl, valeryl andisovaleryl groups, the butyryl, isobutyryl, valeryl disodium salts ofthe compounds of formula I.

17a esters of betamethasone and its 9a-chloro analogue is restricted toonly a certain class of such esters and is thought to depend at least inpart upon the hydrophilic/lipophilic properties of the esters.Surprisingly solubilising by phosphorylation of the 2,1-hydroxy groupstill produces a compound of high topical antiinflammatory action. Evenmore surprisingly the new compounds of this invention possess in generala better ratio of purely anti-inflammatory action to glucocorticoidaction (as measured by thymolytic activity) than the compounds of oursaid prior specification, thereby reducing the risk of undesiredsystemic action should the compound be absorbed following topicalapplication. The compounds according to the invention also possessuseful internal anti-inflammatory action.

The compounds we have discovered according to this invention arerepresented by the general formula (in which R represents an alkanoylgroup containing two to five carbon atoms, acycloalkanoyl groupconraining four, five, six or seven carbon atoms or a benzoyl group, andY represents a fluorine or chlorine atom) and non-toxic water-solublesalts thereof. By the term non-toxic as applied to salts according tothe invention we mean salts with cations which are physiologicallyacceptable for internal or topical administration. Such salts may bemono or dibasic salts.

Those compounds of formula I in which the 16- methyl group is in theB-configuration are preferred on account. of their goodanti-inflammatory activity.

The invention further comprises pharmaceutical compositions for humanand veterinary practice, particularly for use in topicalanti-inflammatory therapy, comprising at least one compound of formula I(as herein before defined) or non-toxic water-soluble salt thereof,together with one or more carriers, vehicles or excipients with orwithout additional therapeutic agents. I

Examples of compositions for topical administration includeointments,lotions, creams, powders and aerosol sprays for application tothe skin; suppositories and retention enemas for the surface treatmentof rectal areas; vaginal inserts; sterile'drops and ointments for eyeand ear treatment; slowly dissolving buccal pellets e.g. for thetreatment of aphthous ulcers; chewing gum providing a slow release ofthe medicament forthe treatment of the mucous membranes of the mouth andthroat; nose and throat sprays and applications.

Skin preparations may, for example, be formulated with compatible bases,for example in conventional manner, to suit the particular conditionsrequired, such as hydrophobic ointments; non-aqueous hydrophilicointments and creams; aqueous creams and lotions either as solutions,suspensions or emulsions, which may if desired contain thickeningagents, humectants etc. Conventional excipients and formulating agentsinclude for example, animal, vegetable andmineral oils and fats and oilyesters e.g. lanolin and its derivatives, arachis oil, the paraffins,isopropyl myristate; non-ionic surfactants such as polysorbate 80 U.S.P.and polyethylene glycols; and humectants e. g. propylene glycol andsorbitol. Preservatives such as for example a chlorocresol andthiomersalate may also be included.

Powder preparations may, for example, contain the steroid in microfineform homogeneously dispersed in a powder base, e.g. mannitol or starch.Suitable propellents for aerosol sprays include dichlorodifluoromethaneand trichlorofluoromethane.

Ointments and drops for eye and ear treatment are preferably formulatedin unit dosage form in single dose capsules or small containers to avoidcrossinfection. Aphthous ulcer pellets may be prepared with a hardsmooth base containing for example, lactose and gelatine or gumtragacanth. Chicle gum with sugar and ion may if desired be added to thesteroid preparations detailed above for therapeutic advantage.

The proportion of active steroid in the topical compositions accordingto the invention will depend upon the precise nature of the formulation,but will generally be within the range of 0.0001 5 percent by weight,advantageously 0.001 -0.5 percent by weight and preferably 0.01 0.25percent by weight.

The preparations may be administered once daily or more frequentlydependent upon the nature of the condition being treated. Particularlybeneficial results may be obtained in some cases by the use of occlusivedressings when the steroid is applied to the skin.

Veterinary preparations are in general, formulated in analogous mannerto those mentioned above, but with suitable adaption made for dose andsize of the animals concerned. The steroid compound according to theinvention may also be useful in intramammary preparations.

Compositions according to the invention also include compositions forthe systemic absorption of the active compounds, for example, oral andparenteral compositions. Since the compounds according to the inventionare highly potent, unit dosage forms are generally preferred. Convenientunit dosage forms for. internal administration include tablets andcapsules and these may, if desired, be formulated to give a sustainedrelease of the active material. Alternatively, readily soluble tabletsmay be prepared from the sodium salt of the steroid to provide a rapidaction. For parenteral use, convenient unit dosage forms includeampoules and vials, the latter being either single or multiple dosecontainers. Suppositories for systemic absorption may be prepared, forexample using a convenient suppository base in conjunction with asuitable carrier to aid absorption from the colon. e.g. sorbitanmonostearate and cholesterol.

Compositions according to the invention for internal administration, mayalso include additional active ingredients such as antibacterial agents,e.g. neomycin; preservatives, such as benZalkonium chloride; suspendingagents such as hydroxyethylcellulose and sorbitol; stabilising andbuffering agents; surfactants etc. Excipients for solid preparationssuch as tablets may include sugar and sugar alcohols e.g. lactose andsorbitol; starch, and lubricants such as magnesium stearate orpolyethylene glycol 6000. Liquid vehicles for compositions for oraladministration may include aqueous or non-aqueous media such as edibleoils which may be treated and flavoured. Sterile vehicles for parenteraluse include water for injection B. P. or isotonic saline and non-aqueousvehicles such as non-toxic oils e.g. arachis oil and propylene glycol.Compositions for parenteral administration may also be prepared assterile dry solids for reconstitution with a sterile diluent, im-.. 1mediately before use.

Preparations for systemic use in unit dosage form may contain from 0.05to 2.0 mg, preferably 0.25 to 1.0 mg, of the active steroid per unitdosage. Generally the on the type of preparation involved. in veterinaryprep- 60. preparations for internal administration may contain from 0.01to 50 percent of active ingredient, dependent and various conventionalmethods of phosphorylation applied to the parent 21-hydroxy compoundshave given only small yields.

However we have found according to a further feature of the inventionthat, quite generally, 21- dihydrogen phosphates ofl7a-acyloxy-20-keto-2lhydroxy steroid compounds and particularly suchcompounds of the pregnane and allopregnane series, may be prepared byreacting the parent 21-hydroxy steroid with phosphorus oxychloride, inthe presence of a tertiary amine, and hydrolysing the resulting 21-dichlorophosphoryl compound to the desired ester or salt thereof.

This process is particularly useful for the preparation of 2l-phosphateesters of 17a-acyloxy steroid compounds of the pregnane seriespossessing antiinflammatory activity and containing in the steroidnucleus, substituents imparting such activity. Thus, antiinflammatorycompounds of the pregnane series are well-known to comprise a keto groupat the 3-position, a double bond at the 4-position or 1- and4-positions, either a keto group or a hydroxy group in thefi-configuration at the ll-position and a keto group at the 20-position. As is well known other substituents may also be present whichenhance or modify the physiological activity of the anti-inflammatorysteroids e. g. a halogen atom, e.g. fluorine or chlorine, at the9-position, an alkyl group, e.g. a methyl group, or a methylene group atthe l6-position, the said alkyl group being in either the aor B-configuration. Other substituents which may be present include methylgroups or fluorine atoms at position 2 and/or 6. The process isespecially applicable to the preparation of the novel steroid compoundsrepresented by formula I (as herein before defined).

It has been found that the use of an inert solvent, e.g. an ether, suchas diethyl ether, tetrahydrofuran or dioxan, or a chlorinatedhydrocarbon such as methylene chloride or chloroform, in the reaction ofthe 2 l hydroxy steroid with the phosphorus oxychloride is especiallyadvantageous.

The tertiary amine employed in the foregoing process is preferablypyridine, triethylamine, N-methyl morpholine, dimethylaniline etc. Thephosphorus oxychloride is advantageously used in a molar excess basedupon the steroid starting material, an excess of at least 3 andespecially 4-5 molar equivalents being preferred. The tertiary amine ispreferably present in at least an equimolar proportion, based upon thesteroid starting material. Moreover, it has been found that the presenceof a molar excess of tertiary amine is advantageous in the reaction ofthe phosphorous oxychloride and the 21- hydroxy steroid. The reaction ispreferably effected at ambient temperatures or with slight cooling, forexample at about -5C. The resulting reaction mixture is generallyhydrolysed to obtain the 2l-dihydrogen phosphate, for example, bytreating the reaction mixture with water, a large excess thereof beingpreferred.

The basic salts of the 21-dihydrogen phosphates of thel7a-acyloxy-20-keto-2l-hydroxy compounds of thepregnane series may beprepared in conventional manner from the parent 2l-dihydrogen phosphatese.g. by reaction with the corresponding base, e.g. an alkali metalhydroxide. However, the basic salts may alternatively be prepareddirectly from the dichlorophosphoryl ester (obtained by the reaction ofthe steroid starting material with phosphorus oxychloride) by conductingthe hydrolysis thereof in the presence of the corresponding base.

The compounds of formula 1 (as hereinbefore defined) may also beprepared by reaction of the parent 2l-hydroxy steroid withpyrophosphoryl chloride, followed by hydrolysis of the intermediate 21-dichlorophosphoryl steroid compound, either to the free phosphate esteror a salt thereof. The reaction of the parent steroid withpyrophosphoryl chloride is advantageously effected in a solvent mediumsuch as for example tetrahydrofuran, dioxan, acetonitrile, aliphatic oraromatic hydrocarbons such as benzene, toluene or xylene; an excess ofpyrophosphoryl chloride may also serve as the solvent. The reaction isconveniently effected at temperatures between 50C and 20C e.g. atambient temperature or with slight cooling, for example, at between and0C. After completion of the reaction, the reaction mixture is hydrolysedby treatment with water preferably in excess and, if it is desired toproduce a salt directly, inthe presence of a basic compound such assodium hydroxide, potassium hydroxide or lithium hydroxide.

Alternatively,the basic salts of the compounds of formula I may beprepared in conventional manner from the parent 2l-dihydrogenphosphates, e.g. by reaction with the corresponding base, e.g. an alkalimetal hydroxide.

For a better understanding of the invention, thefollowing Examples aregiven by way of illustration only:

' phate A solution of 9a-fluoro-l 1B,2l-dihydroxy-l7- isobutyryloxy-lfi-methylpregna-l ,4-diene-3 ,20-dione (2.0 g.) in dry tetrahydrofuran(50 ml.) was added dropwise to a stirred solution of pyrophosphorylchloride (1.27 ml.) in dry tetrahydrofuran (20 ml.) at 0 to 5C. After 3.hours at 0 to 5C the reaction mixture was diluted with ice cold water(120 ml.) and the tetrahydrofuran evaporated in vacuo. The oily productwhich separated was extracted with ethyl acetate, washed with water andevaporated. The residue was dissolved in methanol (40 ml.) and water (30ml.) and the pH adjusted to 9.0 by the addition of dilute sodiumhydroxide solution. The basic solution was diluted with more water andwashed with ethyl acetate and then acidified with ZN-hydrochloric acidto afford an oil which was extracted with ethyl acetate. Evaporation ofthe solvent in vacuo from the washed extract gave the crude productwhich was crystallized twice from aqueous methanol to affordbetamethasone l7-isobutyrate 21-dihydrogen phosphate m.p. 167-170C,(Kofler), [Q]D+6-S.SOM(C 1.0, dioxan) 1C 237 nm (a 15,200)

(P5056; c, 55.7;11, 6.5; P, 5.5. c,,,'1-ig;'F6, J 1 H 013- quires C,55.7; H, 6.8; P, 5.5%).

EXAMPLE 2 Betamethasone l7-valerate Zl-dihydrogen phosphate.

Phosphorus oxychloride (40 g.) was added to a stirred solution ofbetamethasone l7-valerate (20 g.) in dry tetrahydrofuran (400 ml.) andthe mixture cooled to between 0 and 5C. Pyridine (3.4 ml.) was added andthe temperature allowed to rise slowly over a period of 3.5 hours toroom temperature. After a further 3 hours at room temperature themixture was kept at 0C overnight and then for another 3 hours at roomtemperature. Dilution with cold water (1 1.) and evaporation in vacuo ofthe tetrahydrofuran afforded an oil which was extracted with ethylacetate. The washed extract was evaporated in vacuo and the residual oildissolved in aqueous methanol and N-sodium hydroxide solution added topH 9.0. The basic solution was washed with ethyl acetate, acidified with2N- hydrochloric acid and the precipitated oil re-extracted into ethylacetate. Evaporation of the solvent afforded the crude product whichafter two crystallizations from acetone 'yielded betamethasonel7-valerate 2ldihydrogen phosphate (12.42 g.) m.p. 160 163 (Kofler),[01],, 60.1 (C 1.0 dioxan) X 238 nm (6 16,200) (Found: c, 56.8; H, 7.0;P, 5.3. C,,H,,P0,P. 11-1 0. 0.75 CH .CO.CH requires C, 56.8; H, 7.3; P,5.3%). The presence of water and 0.75 mole acetone was confirmedspectroscopically.

The finely ground betamethasone 17-va1erate 21- dihydrogen phosphate(25.1 g.) was suspended in water (200 ml.) and stirred whilst N-sodiumhydroxide solution was added until pH 9.0 was reached. The clearsolution was filtered and freeze-dried to afford betamethasonel7-valerate 21-disodium phosphate [01],, 76.8 (c 1.0, diox a n) Amu 237un (e 14,700) (P ound: C, 49.5; H, 6.0. c,,H,,FNa0,,P.3H o requires C,49.5; H, 6.5%).

EXAMPLE 3 9a-Chloro-1 lB-hydroxyl 7-,2l-( l -isopropy1-lmethoxymethylenedioxy)-16B-methylpregna-1 ,4- diene-3,20-dione Asolution of 9a-chloro-l6fl-methyl-1 18,17,21-trihydroxypregna-l,4-diene-3,20-dione (500 mg.) in dioxen (20 ml.) wastreated with methyl orthoisobutyrate (1.0 ml.) and toluene p-sulphonicacid (25 mg.). After being kept at room temperature for about 30 minutesthe reaction mixture was poured into dilute sodium bicarbonate solutioncontaining a few drops of pyridine and extracted into ether. The extractwas washed with water, dried (MgSO and after the addition of a drop ofpyridine, evaporated in vacuo. Trituration of the residue with coldether gave the crude orthoester which was recrystallized fromether-acetonepetroleum ether to afford 9a-chloro-16B- methylprednisolone17 ,2 1 methyl orthoisobutyrate "1-2 lfr [9l9t f J $29291 239 P 15,500(Found: c, 65.6; H, 7.5;'ci, 713i c',',n,,e1o, requires C, 65.8; H, 7.6;Cl, 7.2%). b. 9a-Chloro-l 113,21-dihydroxy-l7-isobutyryloxy-16B-methylpregnal ,4-diene-3 ,20-dione Uncrystallized9a-chloro-16B-methylprednisolone 17,21-methyl orthoisobutyrate (1.42 g.)in acetone (25 ml.) was treated with water (3 ml.) and 2N-sulphuric acid(0.3 ml.). After being kept at room temperature for 30 minutes thesolution was poured into dilute sodium bicarbonate and the precipitatedsolid removed by filtration. This wet product was dissolved inchloroform, dried (MgSO and the solvent removed in vacuo.Crystallization of the residue from acetonepetroleum ether afforded9a-chloro-l6B-methylprednisolone 17-isobutyrate m.p. 200210 decomp.al.1551905,? (c. .01. dan 38-2 0 (15,300) (Found: C, 65.0; H, 7.2, Cl,7.65. C I-1 C10 requires C, 65.2; H, 74; Cl, 7.4%). c. 9a-Chlorol6B-methylprednisolone 1 7-isobutyrate 2 l dihydrogen phosphate.

Pyrophosphoryl chloride (1.27 ml) in tetrahydrofuran (20 ml.) wasstirred at -50C whilst a solution of Qa-chloro- 1 ofi-methylprednisolonel7-isobutyrate (2.0 g.) in tetrahydrofuran (50 ml.) was added dropwiseover a period of 15 minutes. The temperature was allowed to rise to 10Cand the reaction mixture was kept at this temperature for 4 hours.Dilution with water and evaporation of the tetrahydrofuran in .vacuogave an oil which crystallized on keeping at C overnight. Filtration ofthis material and crystallization from aqueous methanol afforded9a-chloro-l6l3- methylprednisolone l7-isobutyrate ZI-dihydrogenphosphate (1.2 g.) m.p. l78l8l decomp. (Kofler), 9 10 d xasmw. 2.381421,9.192999) (Found: C, 52.6; H, 6.3; P, 5.0. C H CIO P. 2H O requires C,52.5; H, 6.8; P, 5.2%).

EXAMPLE 4 151960) (Found: c, 67.7; H, 7.7.c,,H,,F'o; requires C,

1,4-diene-3,20-dione (2.0 g.) in tetrahydrofuran (50.

ml.) was added over a period of 15 minutes to a solution ofpyrophosphoryl chloride at 50C. The temperature was allowed to rise to--10C and was then kept constant for 3.5 hours. After dilution with coldwater the tetrahydrofuran was removed in vacuo and the precipitated oil,which crystallized on standing, was removed by filtration.Recrystallization from aqueous methanol afforded dexamethasonel7-isobutyrate 2ldihydrogen phosphate (1.78 g; 76% Yield) m.p. l72 l75decomp. (Kofler), [a],, 37.5 (c 1.0, digxanbjtmm. 238 nm (6 16,700),(Found: C, 5 5. 3 l:l, 6.7; P, 5.4. C H FO P. H O requires C, 55.7; H,6.8; P, 5.5%).

EXAMPLE 5 Prednisolone l7-propionate 2l-dihydrogen phosphate.

Phosphorus oxychloride (1.8ml) and then pyridine (0.28 ml) was added toa stirred solution of prednisolone l7-propionate (1.5g.) intetrahydrofuran (40 ml). at 0 5C and the reaction mixture then allowedto come slowly to room temperature. After 6.5 hrs. the

solution was poured into water, the tetrahydrofuran was removed invacuo, and the crude product isolated by extraction with ethyl acetate.This material, in aqueous methanol, was titrated with 0.1 N-sodiumhydroxide to pH 9.0 and the solution extracted with ethyl acetate. Theaqueous solution was acidified to pH 1 with 2N-hydrochloric acid andthen extracted with ethyl acphate was dissolved in methanol 10 m1) andwater (25 ml) and titrated to pH 9.0 with 0.1 N-sodium hydroxidesolution. The clear solution was diluted with more water (100 ml) andfreeze-dried to afford prednisolone l7-propionate 2l-disodium phosphate(280 mg) A max 242 nm (6 14,150) (Found: C, 48.3; H, 5.6; P, 4.9. C l-1,Na,O,P. 3H O requires C, 48.4; H, 6.3; P, 5.2%

EXAMPLE 6 Betamethasone l7-acetate 21-dihydrogen phosphate.

A solution of betamethasone l7-acetate (2.0g) in tetrahydrofuran (70 ml)was added to a solution of pyrophosphoryl chloride (1.27 ml) intetrahydrofuran (20 ml) at 5 to 0C over a period of about 15 minutes.The temperature was kept between 5 and 0C for 3 hours and then thesolution was poured into water and the tetrahydrofuran evaporated invacuo. The mixture was cooled for 1 hour and the crystalline dihydrogenphosphate (1.9 g: 80%) removed by filtration. Recrystallization fromaqueous acetone afforded betamethasone l7-acetate 2l-dihydrogenphosphate m.p. 192 -l94C (Kofler), [11],, 67.3(c 1.0 dioxan), k max 238nm (6 15,400) (Found: C, 53.0 H, 6.4; P, 6.0. C H F0 P. 1.5 H 0 requiresC, 53.2: H, 6.5: P 5.7%).

EXAMPLE 7 Betamethasone l7-propionate (2.0 g) in tetrahydrofuran (90 ml)was added to a stirred solution of pyrophosphoryl chloride (1.27 ml) intetrahydrofuran (20 ml) at 50C. The temperature was allowed to riseslowly to 10C where it was held for 5 hrs and then allowed to rise to 4Cfor 18 hours. Dilution of the mixture with water and evaporation of thetetrahydrofuran in vacuo gave an oil whichwas extracted into ethyl ace-1 tate. Evaporation of the washed extract and two crystallisations ofthe residue from ethyl acetate afforded betamethasone l7-propionate2l-dihydrogen phosphate m.p. 171 173 (Kofler), [a] 66.0(c 1.0, dioxan)(Found: C, 54.9: H, 6.2: P, 5.9 C, H, FO,P. H 0 requires C, 54.9: H,6.6; P, 5.7%).

EXAMPLE 8 Betamethasone 17-butyrate 2l-dihydrogen phosphate.

A solution of betamethasone l7-butyrate (4.0 g) in tetrahydrofuran ml)was added with stirring to a solution of pyrophosphoryl chloride (2.55ml) in tetrahydrofuran at to 0C. After 3 hours the solution was pouredinto water (200 ml) and the organic solvent removed in vacuo. Theprecipitated-oil which solidified on standing was removed by filtration,dissolved in methanol (85 ml) and water (40 ml) and titrated with0.-lN-sodium hydroxide to pH 9.0. Neutral material was removed byextraction with ethyl acetate and the aqueous layer acidified withZN-hydrochloric acid to pH 1. Traces of ethyl acetate were removed invacuo and the crystalline dihydrogen phosphate (3.71 g) removed byfiltration. Recrystallisation from isopropyl ether-methanol affordedbetamethasone l 7-butyrate ZI-dihydrogen phosphate m.p. 173- 177C.(Kofler), [01] 65.5 (c 1.0 dioxan) A max 238 nm (2 15,800) (Found: C55.0; H, 6.6; P, 5.1. C H FO P. 1.5 H 0 requires C, 54.8: H, 6.9; P,5.4%).

A portion of the dihydrogen phosphate 1 g) was suspended in water andslowly titrated with 0.1N-sodium hydroxide solution to pH'9.0. Theresulting solution was freeze-dried and the product crystallised fromaqueous acetone to afford betamethasone 17-butyrate 2l-disodiumphosphate [11],, 54.0 (c 1.0 Cl-lCl EXAMPLE 9 Betamethasone l7-benzoate21-dihydrogen phosphate Phosphorus oxychloride (1.6g.) was added to asolu- Betamethasone l7-valerate 2l-dihydrogen phosphate 0.05% in equalparts of Macrogol Ointment B.P.C. and polyethylene glycol 1,500.

Trituratethe finely divided active material with a little of theointment base and gradually dilute with the remaining base to give evendistribution.

EXAMPLE (c) Aqueous Cream Betamethasone 17-valerate 2l-disodiumphosphate Cetostearyl alcohol B.P.C. 7.2% "/w Cetomacrogol 1000 B.P.C.1.8% "/w Liquid paraffin 6.0% "/w White soft paraffin 15.0% '"lwChlorocresol 0.1% /w Distilled water to produce 100 parts by weightDissolve the chlorocresol in 60 parts of heatsterilised water at about90C. and cool to 65C. Dissolve the active ingredient in the remaining 10parts of cold sterilized water. Melt together the oily phaseconstituents to 90C. and cool to 60C. Add the oily phase to thechlorocresol solution, stirring rapidly until the emulsion cools andthickens at about 40-45C. Slowly incorporate the betamethasone17-valerate 21- phosphate solution and continue to stir the mix at slowtion of betamethasone l7-benzoate (801 mg.) in dry tetrahydrofuran andthe mixture cooled in an ice-salt bath. Pyridine (0.13 ml.) was addedand the tempera ture was allowed to rise slowly to room temperature.When the reaction was judged complete (thin layer chromatography) thereaction mixture was poured into water and the tetrahydrofuranevaporated in vacuo. The oily material which became solid on triturationwas removed by filtration. This pale yellow solid was suspended inaqueous methanol and 0.1N-sodium hydroxide solution addedto pH 9.0. Theaqueous solution was extracted with ethyl acetate and then acidifiedwithdilute hydrochloric acid and the precipitated material extractedwith ethyl acetate. Evaporation in vacuo of the solvent afforded an oilwhich was recrystallized from a large volume of ether to givebetamethasone 17- benzoate 2l-dihydrogen phosphate. m.p. l87l90C(Kofler), [a],, 49.8 (c 0.7 dioxan).

The following examples illustrate the preparation of pharmaceuticalcompositions according to the invention.

EXAMPLE (a) Hydrophobic ointment 1. Betamethasone l7-valerate 2l-dihydrogen phosphate 0.1% /w i 2. Neomycin sulphate B.P. 0.5% /w 3.Liquid paraffin B.P. 10% "/w 4. White soft paraffin B.P. to 100 parts byweight Ball mill component 1) to a particle size not exceeding 10microns with a small quantity of heat-sterilised liquid paraffin, usingthe remainder of the liquid paraffin to rinse out the mill. Add thesuspension to the previously sterilised component (4) warmed to a softmelt at about 37C. and incorporate component (2) therein, stirring witha planetary mixer until the active ingredients are evenly distributedand the ointment thickens at about C. Fillinto' sterilised tubes.

EXAMPLE (b) Hydrophilic non-aqueous skin application speed until thecream sets at about 30C. Fill into sterilized pure tin tubes.

EXAMPLE (d) Lotion Betamethasone 17-valerate 2l-disodium phosphate 0.05%/W Carbopol 934* (T.M.) 0.3% "/w Diethanolamine approx. 0.5% /wDistilled water to produce 100 vols *(Carboxy vinyl polymers, suppliedby B.P. Goodrich Chemical Co. through Honeywill and Stein Ltd,Devonshire House, Mayfair Place, London, W.1.

Disperse the Carbopol 934 in 90 volumes of water, heat to C. for 10mins.and allow to cool to room temperature. Add the diethanolamine slowly,while stirring until thickening occurs and the mix has a pH of 6.8 7.0.Dissolve the active ingredient in the remaining water, previously boiledand cooled, add to the 10- tion base and mix well.

EXAMPLE (e) Aerosol spray l. Betamethasone 17-valerate 2l-disodiumphosphate 50mg 2. Fractionated coconut oil to 1.20g.

3. Dichlorodifluoromethane 16.32g.

4. Trichlorofluoromethane 24.48g.

Ball mill component (1) with a small quantity of component (2) (both ofwhich have previously been 'dried to constant weight ina desiccator), toa particle size of about 0.5 to 5 microns. Dilute the suspension withthe remaining oil, mix well and distribute into suitable pressurecontainers. Add the propellants in a conventional manner and check thefilled weight and actuator.

EXAMPLE (f) Retention enema Betamethasone 17-valerate 21-disodiumphosphate 0.001% /w Nipastat*T.M. 0.10% "/v Distilled water to produce100 volumes (*A mixture of methyl, ethyl, propyl and butyl esters ofphydroxybenzoie acids from NIPA Laboratories Ltd; Treforest TradingEstate, near Cardiff, Wales.

l-leat-sterilise the water and while still hot dissolve in it theNipastat. Cool and add the active material and stir until dissolved.Distribute in quantities of 100 ml into conventional plastic bags forsimple administration.

EXAMPLE (g) Eye and Ear Drops Betamethasone l7-valerate 2l-disodiumphosphate Thiomersalate B.P. 0.005% "/v Sodium chloride 0.6% "/v Waterfor Injection B.P. to 100 vols.

Dissolve the solids in the water for injection; resterilise the solutionby passage through a membrane filter and fill aseptically into smallamber sterile vials provided with suitable eye droppers.

EXAMPLE (h) Aphthous Ulcer Pellets Betamethasone l7-valerate2l-dihydrogen phosphate 0.5mg.

Lactose 75.7mg.

Magnesium stearate 0.8mg.

Acacia 3.0mg.

Grind the active ingredient to a very small particle size of about ,1-microns and gradually dilute with the lactose. Make a 25 percentsolution of the acacia in water, heat to boiling and cool. Use thissolution to granulate the powder mix, pass through a No. 12 mesh B.S.sieve and dry to constant weight in a vacuum oven at 45C. Pass the driedgranules through a No. 20 mesh B.S. sieve and blend in the magnesiumstearate. Subject the granules to heavy compression with /32 inchbiconvex punches to form 80 mg pellets. Protect the tablets frommoisture and light.

EXAMPLE (i) Nose and Throat Spray 1. Betamethasone l7-valerate21-disodium phosphate 0.01% /V 2. Neomycin sulphate 0.5% "/v 3. Sodiumchloride 0.5% IV 4. Distilled water to produce 100 vols.

Sterilise the distilled water by heat, and when cool dissolve in itcomponents (2) and (3). Adjust the pH to 6.8-7.0 using sodium hydroxideand to this solution add component (1) and stir to dissolve. Filter andfill into small, well filled plastic containers with adaptable spray ordropper nozzles. Protect from light.

EXAMPLE (j) Oral tablet.

l. Betamethasone l7-valerate 21 dihydrogen phosphate 0.5mg.

2. Lactose B.P. 78.5mg.

3. Acacia Powder B.P. 5.0mg.

4. Maize starch 10.0mg.

5. Potato starch 5.0mg.

6. Magnesium stearate 1.0mg.

Reduce the particle size of component (1) to less than 10 microns indiameter and substantially to about 1 to 5 microns. Blend togethercomponents 2,3 and 5 and dilute component (1) with the mixture bytrituration. Granulate the powders with component (4) as a 10 percentstarch paste and pass the mass through a No. 12 mesh B.S. sieve. Dry thegranules at 37-40C. to constant weight and sift through a No. 16 meshB.S. sieve. Lubricate the granules with component (6) and compress onone-fourth inch diameter punches into mg. tablets. The tablets may becoated using a readily dispersible film coating.

We claim:

1. A compound of the formula on, 'Y

represents an alkanoyl group selected from the group consisting ofbutyryl, isobutyryl, valeryl and isovaleryl.

5. A compound as claimed in claim 1 selected from the group consistingof betamethasone l7-isobutyrate 2l-dihydrogen phosphate; betamethasonel7-valerate 2 l -dihydrogen phosphate; 9a-chloro- 1 6B-methylprednisolone l 7-isobutyrate 2 l-dihydrogen phosphate;dexamethasone l7-isobutyrate 2 l dihydrogen phosphate; betamethasonel7-acetate 2ldihydrogen phosphate; betamethasone l7-propionate2l-dihydrogen phosphate; betamethasone l7-butyrate 2l-dihydrogenphosphate; betamethasone l7-benzoate 2l-dihydrogen phosphate; and anon-toxic watersoluble salt thereof.

6. A compound as claimed in claim 1 in the form of its sodium orpotassium salt.

l i 4 I I 133 3 UNITED STATES PATENT OFFICE CERTKFICATE OF CORRECTIONPatent No. 3,764,616 Dated October 9, 1973 InV8ntOr(S) Joseph Elks,Peter John May and Gordon Hanley Phillipps It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

On the Title Page, Column 1, line 12, "October 18, 1968" should readOctober 14. 196 8 Signed and sealed this 16th day of April 1971 (SEAL)Attest:

EDWARD I LFLETGHERJR. C MARSHALL DANN Attesting Officer Commissioner ofPatents

2. A compound as claimed in claim 1 in which the 16-methyl group is inthe Beta -configuration.
 3. A compound as claimed in claim 1 in which Yrepresents fluorine.
 4. A compound as claimed in claim 1 in which R1represents an alkanoyl group selected from the group consisting ofbutyryl, isobutyryl, valeryl and isovaleryl.
 5. A compound as claimed inclaim 1 selected from the group consisting of betamethasone17-isobutyrate 21-dihydrogen phosphate; betamethasone 17-valerate21-dihydrogen phosphate; 9 Alpha -chloro- 16 Beta -methylprednisolone17-isobutyrate 21-dihydrogen phosphate; dexamethasone 17-isobutyrate21-dihydrogen phosphate; betamethasone 17-acetate 21-dihydrogenphosphate; betamethasone 17-propionate 21-dihydrogen phosphate;betamethasone 17-butyrate 21-dihydrogen phosphate; betamethasone17-benzoate 21-dihydrogen phosphate; and a non-toxic water-soluble saltthereof.
 6. A compound as claimed in claim 1 in the form of its sodiumor potassium salt.